Overview

Pathogenicity: Frontotemporal Dementia : Not Classified
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr14:73211868_73211869 --->CGC
Position: (GRCh37/hg19):Chr14:73678576_73678577 --->CGC
dbSNP ID: rs63750762
Coding/Non-Coding: Coding
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Codon Change: CGC.TCT to CGC.CGC.TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was identified in a kindred with three cases of dementia, in which the proband had symptoms typical of frontotemporal dementia and parkinsonism (FTDP). Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions. Analysis of the progranulin gene identified a G to A mutation in the exon 1 splice donor site (IVS1+1G-->A) predicted to destroy the 5'-splice site of exon 1 and completely block progranulin production. Thus, the effects of this PSEN1 mutation remain unknown and may be non-pathogenic (Boeve et al., 2006). In a subsequent study, the variant was described as most likely having reduced penetrance, with an allele count of four, and a frequency of 0.0014 percent in the gnomAD variant database (Koriath et al., 2018).

Neuropathology
Unknown.

Biological effect
The mutation is an in-frame insertion of 3 nucleotides in exon 10 resulting in the addition of an arginine between amino acids R352 and S353. Aβ CSF and plasma levels in the proband were roughly normal (Tang-Wai et al., 2002). In cultured cells, expression of the mutation increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42 (Amtul et al., 2002). Moreover, in an vitro assay using purified proteins to test the ability of the mutant to cleave the APP-C99 substrate, production of Aβ42 was markedly reduced and that of Aβ40 was undetectable (Sun et al., 2017).

R352 is not conserved between PSEN1 and PSEN2, and in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021).

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References

Paper Citations

1. Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Josephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC. Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain. 2006 Nov;129(Pt 11):3103-14. PubMed.
2. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
3. Tang-Wai D, Lewis P, Boeve B, Hutton M, Golde T, Baker M, Hardy J, Michels V, Ivnik R, Jack C, Petersen R. Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord. 2002;14(1):13-21. PubMed.
4. Amtul Z, Lewis PA, Piper S, Crook R, Baker M, Findlay K, Singleton A, Hogg M, Younkin L, Younkin SG, Hardy J, Hutton M, Boeve BF, Tang-Wai D, Golde TE. A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002 Mar;9(2):269-73. PubMed.
5. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
6. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading